The Adams comprise a new family of proteins that contain a disintegrin and a metalloprotease domain. Given that they are expressed at cell surfaces and that, as a group, they possess four potential functions- metalloprotease, adhesion, fusion and signaling- they are poised to play important roles in development and disease. The long-term goal of this work is to elucidate the roles of the four ADAM functional domains in cell- matrix interactions that guide development and lead to disease. Recent work has shown that ADAMs participate in important developmental events (e.g., fertilization, myogenesis, neurogenesis_ and that ADAM disintegrin domains can interact with integrins. These observations lead o the central hypothesis of this proposal: that adhesive events mediated by ADAM disintegrin domains transmit signals by binding to integrins and (ii) that ADAM disintegrin domains direct other ADAM functional domains to target sites. The major goal of this proposal is to test these hypotheses. The specific aims are: 1. To further characterize the interaction between ADAM disintegrin domains and integrins: 2. To test the hypothesis that ADAM disintegrin domains transmit signals through integrins; 3. To test the hypothesis that ADAM disintegrin domains direct ADAM metalloprotease domains to target substrates; 4. To test hypothesis that ADAM disintegrin domains direct ADAM fusion domain to target membranes. The experimental design is modeled on previous studies of disintegrins, integrins, integrin-medicated signaling, and viral adhesion/fusion proteins. It will employ a combination of biochemical, as eschewal, molecular, and developmental biological approaches. In addition to its basic reverence to the roles of ADAM disintegrin domains in cell and developmental processes (e.g., fertilization and neurogenesis), the project has a high degree of health relatedness. For example, the dual functions of ADAMs as both adhesion molecules and as proteases suggests that they may be key players in the de-adhesive, migratory, and re-adhesive activities involved in tumor metastasis.